Influence of methyl donor nutrients as epigenetic regulators in colorectal cancer: A systematic review of observational studies

Table 1 Characteristics of the eight case-control studies included in this systematic review examining the interactive effects between single-nucleotide polymorphisms in genes encoding methyl-metabolizing enzymes and one-carbon metabolism-related dietary compounds on colorectal cancer risk

Ref.	Country	Age (yr)	No. cases (M/W), endpoint	No. controls, type	Gene (SNP)	Nutrient/alcohol	Method for measuring nutrition intake	Outcome (OR, 95%CI)			Adjustments to OR	NOS
								SNP	Nutrient/alcohol	Interaction
Chen et al[23]	United States	40-75	144 M, CRC	627 C	MTHFR (677C>T)	Dietary folate, Met, and alcohol	Validated FFQ (self-reported)	No assoc	Alcohol (≥ 5 vs ≤ 1 drinks/wk): 1.61 (1.01-2.58)	677TT (vs CC/CT)-low alcohol consumption (≤ 1 drinks/wk): 0.11 (0.01-0.85) (P-interac = 0.02)	Age, CRC family history	7
Guerreiro et al[24]	Portugal	Cases (64.2 ± 11.3), controls (62.2 ± 12.1)	104/92 CRC	200 C	MTHFR (677C>T), MS (2756A>G), SHMT (1420C>T)	Dietary folate, vitamins B6 and B12, glycine, Met, serine, and alcohol	Validated FFQ (by interview)	677TT (vs CC/CT): 3.01, (1.3-6.7); 1420TT (vs CC/CT): 2.6, (1.1-5.9)	Folate (> 406.7 mcg/d vs < 406.7 mcg/d): 0.67 (0.45-0.99)	677TT (vs CC/CT)– folate (< 406.7 mcg/d): 14.0, 1.8-108.5 (P = 0.05)	Age, CRC history, and sex	5
Kim et al[25]	Korea	30-79	465/322 CRC (363 CCa, 330 RCa)	656 H	MTHFR(677C>T)	Dietary folate and alcohol	Validated FFQ	677TT (vs CC/CT): 0.60 (0.46-0.78)	Folate (high vs low intake): 0.64 (0.49-0.84); alcohol (high vs low intake): 1.76 (1.26-2.46)	677CC/CT–Low-methyl diet (folate < 209.69 mcg/d and alcohol ≥ 30 g/d): 2.32 (1.18-4.56) (P-interac = no assoc)	Age, BMI, CRC family history, energy intake, multivitamin use, sex, smoking status	7
Ma et al[26]	United States	40-84	202 M, CRC	326 C	MTHFR (677C>T)	Plasma folate, and alcohol consumption	FFQ (self-reported)	677TT (vs CC): 0.45 (0.24-0.86)	Folate (plasma deficiency vs adequate levels): No assoc	677TT (vs TC/CC)–folate (adequate levels): 0.32 (0.15-0.68)	Age, alcohol consumption, aspirin use, BMI, exercise, multivitamin use, and smoking status	7
									Alcohol: Unk	677TT (vs CC)–alcohol (0-0.14 drinks/d): 0.12 (0.03-0.57)	Age
Murtaugh et al[27]	United States	30-79	446/305 RCa	979 C	MTHFR (677C>T, 1298A>C)	Dietary folate, riboflavin, vitamins B6 and B12, Met, and alcohol	FFQ (by interview)	W, 677TT (vs CC): 0.54 (0.30-0.98). M&W, 1298CC (vs AA): 0.67 (0.46-0.98)	Dietary folate (> 475 mcg/d vs < = 322 mcg/d): 0.66 (0.48-0.92). High methyl donor status (vs low status): 0.79 (0.66-0.95)	No assoc	Age, BMI, ibuprofen use, intake of energy, fibre and calcium, PA, sex, and smoking status	6
Pufulete et al[28]	United Kingdom	38-90	13/15 CRC	76 C	MTHFR (677C>T, 1298A>C), MS (2756A>G), CBS (844ins68)	Plasma folate, vitamin B12, and homocysteine, alcohol and folate intake	Validated FFQ (by interview)	677TT (vs CC): 5.98 (0.92-38.66), P = 0.06; 1298CC (vs AA): 12.6 (1.12-143.70), P = 0.04	Folate status score (T3 vs T1): 0.09 (0.01-0.57), P-trend = 0.01	Unk	Age, alcohol consumption, BMI, sex, and smoking status	7
Sharp et al[29]	United Kingdom		150/114 (189 CCa, 75 RCa)	408C	MTHFR (677C>T, 1298A>C)	Dietary folate, riboflavin, vitamins B6 and B12, and alcohol	Validated FFQ (self-reported)	No assoc	No assoc	677CT/TT (vs CC)–folate (> mean): P-interac = 0.029. 677CT/TT (vs CC)–vitamin B6 (> mean): P-interac = 0.016	Age, CRC family history, energy intake, NSAID use, PA, and sex	6
Slattery et al[30]	United States	30-79	824/849 CC (DCCa 405/303; PCCa 395/327)	1816 C	MTHFR (677C>T)	Dietary folate, Met, vitamins B6 and B12, and alcohol	Validated CARDIA diet questionnaire	677TT: No assoc	Unk	TT-low risk diet (high in folate and Met and without alcohol): 0.4 (0.1-0.9)	Age, BMI, intake of energy and fibre, PA, and smoking intensity	7

Asso: Significant association; BMI: Body mass index; C: Community controls; CBS: Cystathionine synthase; CCa: Colon cancer; CI: Confidence interval; CRC: Colorectal cancer; DCCa: Distal colon cancer; FFQ: Food frequency questionnaire; H: Hospital controls; interac: Interaction; M: Men; Met: Methionine; MS: Methionine synthase; MTHFR: Methylenetetrahydrofolate reductase; NSAID: Nonsteroidal anti-inflammatory drugs; NOS: Quality Newcastle-Ottawa Scale; OR: Odds ratio; PA: Physical activity; PCCa: Proximal colon cancer; RCa: Rectal cancer; SHMT: Serine hydroxymethyltransferase; SNP: Single-nucleotide polymorphism; unk: Unknown; W: Women.